HIV-infected persons on highly active antiretroviral therapy (HAART) experience an increased prevalence and incidence of insulin resistance and fat redistribution, which are both associated with a heightened risk of diabetes and cardiovascular disease. The mechanism of insulin resistance in HIV-infected persons is poorly understood, and most studies have not examined persons based on changes in body fat distribution. The pathogenesis of insulin resistance in persons with central fat deposition vs. peripheral fat atrophy may differ; increased rates of lipolysis may alter fat content in the peripheral muscle and liver, leading to differential effects on peripheral and hepatic insulin sensitivity. A better understanding of insulin resistance in HIV-infected persons will allow targeted treatment and preventive efforts. This K23 Mentored Patient-Oriented Research Career Development Award proposes a translational approach to examine the primary site and mechanism of insulin resistance, using magnetic resonance spectroscopy (MRS), in HIV-infected subjects with either central fat deposition or peripheral fat atrophy. The specific aims of this proposal are 1) To examine peripheral and hepatic insulin sensitivity using eugylcemic hyperinsulinemic clamp and stable isotope infusion in HIV-infected subjects with either central fat deposition or peripheral fat atrophy 2) To measure lipid content in peripheral muscle and hepatic tissue using MRS in HIV-infected subjects with insulin resistance and either central fat deposition or peripheral fat atrophy 3) To obtain preliminary data on the effect of metformin vs. placebo on peripheral and hepatic insulin sensitivity and lipid content in HIV-infected subjects with insulin resistance and central fat deposition, and to assess the effect of pioglitazone vs. placebo on peripheral and hepatic insulin sensitivity and lipid content in HIV-infected subjects with insulin resistance and peripheral fat atrophy. This Career Development Award will allow hands-on laboratory training in glucose/insulin clamp studies, stable isotope methods, and MRS. Didactic coursework will include advanced biostatistics, clinical trial design, and ethics of clinical investigation. Practical experience in conducting an open clinical trial and establishing a data safety monitoring board will also be gained. The coursework, laboratory training, completion of a clinical trial, and multidisciplinary mentoring team will provide a comprehensive and rigorous program for ultimate development as an independent clinical investigator. PUBLIC HEALTH RELEVANCE: Changes in body fat, including fat deposition in the trunk, neck, chest, and upper back (central fat deposition) and fat atrophy in the arms, legs, and face (peripheral fat atrophy) were described soon after the introduction of highly active antiretroviral therapy, as part of HIV lipodystrophy, a syndrome characterized by insulin resistance, dyslipidemia, and body shape changes. The primary site and mechanism of insulin resistance in HIV-infected persons is not well understood, and likely differs by abnormalities in body fat. The objective of this proposal is to use the K23 Mentored Patient-Oriented Research Career Development Award to examine the primary site of insulin resistance in HIV-infected persons with either isolated central fat deposition or isolated peripheral fat atrophy using eugylcemic hyperinsulinemic clamp, stable isotope infusion, and magnetic resonance spectroscopy.